“Can a damaged brain change its own structure and learn to replace lost functions? Conventional neuroscience once said no, but pioneers in the field have achieved miraculous transformations. From his investigation of their work, Norman Doidge tells the story of the perpetually falling woman …. ”

The Division of Psychoanalysis of the American Psychoanalysis Association gives an insightful review of Dr Doidges’ account of the endless powers of brain plasticity with perseverence.

In The role of eicosanoids in the brain: Tassoni et al from Deakin University Australia, remind readers that fish oil is the mainstay of our nervous system at Asia Pac J Clin Nutr. 2008;17 Suppl 1:220-8. “The eicosanoids play important roles in neural function including sleep induction (PGD2), long term potentiation, spatial learning and synaptic plasticity (PGE2), resolution of inflammation (lipoxins) and anti-inflammatory and neuroprotective bioactivity (dihydroxy-docosatriene, neuroprotectin D1, formed from DHA). Additionally, drugs which are used to treat depression have been shown to reduce the turnover of arachidonic acid AA to PGE2 in the brain. Diets deficient in omega 3 PUFA lead to reduced DHA in the brain and increased turnover of AA to eicosanoids, an effect which is overcome by restoring the omega 3 PUFA to the diet. In neural trauma and neurodegenerative diseases, there is a dramatic rise in the levels of AA-derived eicosanoids. In contrast, DHA-derived compounds can prevent neuroinflammation. Clearly, the eicosanoids are very important for the normal functioning of the brain, while the PUFA themselves are important in membrane structure and function.

This was confirmed even in the young women on oral HT OHT for a mean of > 6 years in the Womens’ Health Initiative, and for 9 years in the recent Oulu trial.(Heikkinen ea) .

Masters and Grody already by 1953 in the first RCT of HRT in women aged a mean of 73yrs showed that balanced testosterone: estradiol 20:1 injection for at least 13 months suppresses both breast and endometrial proliferation and restores multisystem health provided degenerative disease was not already too advanced. We have confirmed this for the past decade using a quarter of the dose they used, as longer-acting depot injection eg Mixogen, Primodian Depot.

Moller and Tvedegard Denmark, and Jaffe USA, have shown the protective role of testosterone in cardiovascular disease in men and women; Von Shultz ea at the Karolinska have recently confirmed the protective role of testosterone on the endometrium;

while Clarkson’s group at Wake Forest Univ, and Zhou and Dimitrikakis in Australia, have shown testosterone’s protective role on breast in both primates and women.

Below are many more reasons why it is negligence both to go on prescribing oral HT pills to postmenopausal women, and negligence to deny both men and women lifelong physiological balanced parenteral sex hormone replacement if they have demonstrable sex hormone deficiency/ imbalance on blood levels- irrespective of sexual dysfunction since this is multifactorial (often culture-specific) and often the last thing complained of.

So why encourage women to take even low-dose oral (hepatic first-pass) estrogen plus progestin HT if only for the first 10 years, when permanent parenteral physiological dose testosterone plus estradiol HRT ( arguably with a little progesterone for it’s unique benefits) does only good? (by whatever method the woman chooses and can afford- cream, patch, spray, implant, subcutaneous injection- even as lowdose combined oral micronised T+E+P – Lee Vliet).

It is common cause that no plant – phyto- hormones have been proven to give any of the longterm multisystem benefits of appropriate HRT- and concern remains that, as with kava and black cohosh, there may be rare but deadly adverse liver if not cancer effects.

Since the post-gonadopausal half of life is crucial to every person let alone society, and early and permanent appropriate HRT can make huge difference to dying well, lay counsellors, nurses and the like must be banned from advising, scaring people to the contrary.

In ethical health systems, only qualified and registered health practitioners are allowed to advise and treat serious conditions – and no condition is as serious for aging humans as sex hormone deficiency/ imbalance, since the deficiency is so safely, cheaply (about $5/month in RSA), easily and effectively replaced with human hormones.

It is unethical to neglect to recommend long-proven optimal therapy, especially that which is low-cost and safe. It is farcical to argue, after a million years of evolution and >50 years of safe effective use, that any human hormone replacement in physiological balance for demonstrable deficiency is unproven unless tested in long-term RCTs, when no designer drug (except metformin- 1922) has been proven in RCTS lasting even 5 years to be as safe and effective as appropriate HRT, minerals, vitamins, fish oil and scores of other natural supplements in the chronic prevention of all the major degenerative diseases of aging.

In “European” people CVD kills 20% more women ie 57% vs 43% of men; whereas cancer kills only 17% of women (BRCA 3% vs PRCA 4% of men). Metabolic syndrome is now present in 2/3 of older women; after the menopause, women fatten, get more HBP, lipidemia, IGR, diabetes and thus CVD, so all these risk factors need to be addressed including with appropriate HRT. The management of the menopause is not the exclusive responsibility of the gynecologist “

Never mind crippling prevalent arthritis, obesity, and depression, by 65yrs 80% have raised bloodpressure (>130/85) -which predisposes to heartfailure, hemorrhagic stroke and dementia. In women, use of digoxin is associated with increased all-cause death.

The symptom discomforts of the menopause – for which women consult their gynaecologists , mothers, grannies, aunts, sisters, pharmacies, journalists , herbalists and everyone else – last for about 5 years, then usually pass.. But the non-gynaecological consequences of gonadopause – premature death, or dementia, even major arthritis or hip or spinal or heart failure or stroke – affect probably 90% after the menopause phase is over; and are a permanent loss or crippling disability to the survivors- of which the family, society, family practitioner, internist and orthopaedist, ( not the lay counsellor or surgeon -gynecologist, breast)have to take care .

So the necessity for appropriate permanent HRT is the major longterm concern of everyone but gynecological and breast surgeons and lay counsellors – who deal only with shortterm issues.

When will doctors, and regulators, and our medical schemes, begin to follow evidence-based medicine (instead of dogma – profit) and give women the same appropriate physiologica lhuman hormone replacement as men, instead of hypocritically forcing on the most vulnerable – the postmenopausal woman – what profits only the drug and disease industry? Why should women be forced to take undesirable oral HT that has been known to promote major complications for over 30 years, and to boot produces unnecessary and unwanted menstruation, and suppresses necessary anabolic androgen, and promotes adiposity, fluid retention, hypertension, thrombotic, biliary and breast disease?

Gotmar ea U Linkoping Climacteric.2008 Aug;11(4):304-14.Symptoms in peri- and postmenopausal women in relation to testosterone concentrations: data from The Women’s Health in the Lund Area (WHILA) study) Lower testosterone concentrations were associated with lower quality of life in perimenopausalwomen but not to sexual well-being.

Lin ea London BMJ.2008 Jul 10;337:a386. Gallbladder disease and use of transdermal versus oralhormone replacement therapy in postmenopausalwomen: prospective cohort study. Gallbladder disease is common in postmenopausal women and use of hormone replacement therapy increases the risk. Use of transdermal therapy rather than oral therapy over a five year period could avoid one cholecystectomy in every 140 users

Meyer ea Univ Auckland Osteoporos Int.2008 Jun 19. Change in the use of hormone replacement therapy and the incidence of fracture in Oslo. The reduction in fracture incidence in postmenopausalwomen in Oslo occurred in a period with a substantial increase in the use of HRT

Heikkinen Menopause Int.2008 Jun;14(2):70-7. A 10-year follow-up of the effect of continuous-combined hormone replacement therapy and its discontinuation on bone in postmenopausal women. Low-dose oral ccHRT in postmenopausal women is associated with increases in lumbar spine BMD for at least nine years. These gains are not sustained after cessation of therapy but the rate of BMD loss varies between individuals.

Canonica ea Inserm France BMJ.2008 May 31;336(7655):1227-31. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic ris

Nutrition is becoming increasingly costly as world population mushrooms, and worse, as oil-burning industries immorally pay more (and governments thus get more in taxes) for plant oil as fuel than farmers can get for producing food. The hungry poor majority is irrelevant, despite the fact that there has been superabundance of natural and environmetally friendly power available forever, and harnessable by relatively simple technology (which Industry and governments have criminally suppressed) for decades.

Fish oil omega3 – eicosapentanoic acid EPA and docosahexanoic acid DHA – seems to be the most valuable single nutrition supplement we have, apparently almost halving all major diseases (and mortality) from brain and immune dysfunction in infants and children to all the major common degenerative diseases of aging, from vascular and arthritic to immune and mental.

Plant oils have indispensable benefits. But as people have migrated away from the seaside and fishing, and fish has become scarce so that it is no longer a staple for the poor or as chickenfeed, it is reported that EPA/DHA intake has fallen below 100mg/week in USA. And the more omega6 we eat, and the longer we live, the less EPA+DHA our metabolism can apparently make.

So as diet has improved among the better-off on the Food-Pyramid-recommended higher cereal and nut intake, and livestock has been shifted from pasture-fed (at least some omega3) to grain-fed (high omega6), it is estimated that the historical 6:1 ratio of dietary omega6:omega3 in western diet has actually risen adversely to 20:1.

By contrast, historically those who lived as fisher people reputedly had/have the least chronic aging diseases, and the lowest diet omega6:omega3 ratio, reputedly 1:1.

Oils- including GLA gamma-linoleic acid and ALA alphalinoleic and linolenic acid- are enormously beneficial in humans, especially for immune modulation to steer between hyper immunity – allergy and rheumatic disease- and hypo-immunity – infections and cancer.

But if one eats a prudent Mediterranean-type diet and ensures at least 3gm fish oil i.e. close to a gram of EPA+DHA a day, is it wise or unwise to again increase the already high omega6 excess by encouraging omega6 supplements as in patent products e.g. Effamol?

Most of us older generation were brought up on a spoon of cod liver oil – Scotts Emulsion a day. This custom seems to have fallen into abeyance.

Now it is hard to tell whether this fact – fish oil deficiency – or junk food, or global pollution, or hours of television a day, or the abolition of discipline and obligatory physical exercise at most schools, has contributed more to apparent fall in learning and behaviour achievements in children, and increase in depression, diabetes, overweight, osteoporosis, anxiety, vascular, malignant, inflammatory and dementing diseases.

There is no evidence that patent mixed fish-plus-plant oils do better than fish oil alone in the indisputable improvement in ADHD attention deficit hyperactivity-disorder in children.

Indeed, it should be asked whether, in those on prudent mixed diet and progressively fattening, where fish oil is availableit is not deleterious — adverse to the most vulnerable children- to add, promote supplements of plant oil when only fish oil should be supplemented from cradle to preganancy to grave? The great majority of trials that have been done suggest that adding plant oils gives no extra benefit over fish oil alone– just more excess calories and rise in inflammatory markers.

But capitalism, industry- most of mankind- is driven by profit and especially greed, so there is perverse incentive in promoting manipulated ie patentable, branded supplements and drugs over the optimal natural nutrients- which are the best drugs. Manufacturers and advertisers cannot afford to be idealists; and only diease pays the Disease Industry, now one of the biggest in the world alongside habit-forming drugs like tobacco, alcohol, power-wars – and the entertainment media including commercial “sport” and sex..

Ross & Henderson’s sentinel (JAMA 1980) paper on the strong relationship between long term oral premarin total dose and breast cancer was largely ignored: that with cumulative premarin dose >1,500 mg (ie 7yrs) the breast cancer risk was estimated to be 2.5 in women with ovaries (vs 0,7 sans ovaries); the risk ratio for a high cumulative dose (ie after about 15years, >3mg premarin) rose to 5.7 relative to nonusers with normal breasts.

But at the same time, Finnish papers in Maturitas showed why, because of non-physiological high E1>E2 even on oral E2, systemic ERT is preferred:

1. starting OHT well after age 60yrs and continuing even modest dose cyclic (premarin 0.625mg plus MPA 5mg) does more harm than good; THIS SAYS NOTHING ABOUT APPROPRIATE PHYSIOLOGICAL BALANCED COMBINED PARENTERAL TESTOSTERONE-PROGESTERONE-ESTRADIOL HRT FROM ANY POSTMENOPAUSAL AGE HAVING ANY LIFELONG RISKS WHATSOEVER.

2. starting the same OHT regime soon after menopause – especially premarin alone- reduces all major diseases and mortality by about a third, except for rare cases of deep vein thrombosis and cholelithiasis; this outcome was confirmed in the 9year RCT in Finland (Heikkinen ea 2006) in which women on oral estradiol 1mg/d +- MPA 2.5mg from menopause had zero major adverse events. BUT THIS SPEAKS ONLY FOR AT MOST THE 9 YEARS THAT THESE WOMEN WERE IN THE TRIALS.

Apart from gender-reproduction-childhood growth promotion (ie androgens, estrogens & progestins), their actions fall into many other systemic classes; which in conventional “replacement” doses the literature and experience suggests may be compared as follows:

Muscle anab-olic

Body

fat gain

Bone spar- ing

Mineralocor-ticoid

Immuno-enhancing

cancer prom-oting

Infec- tion risk

Mood & mind

1 Calciferols

+

+

+

modulating

–

–

+

2 TT, DHEA

+

inner

++

+

modulating

–

–

+++

3 Estradiol E2

– (or n)

outer

+

+

enhancing

+

–

+

4 progestin

N

n

n

+

modulating

–

–

++

5 Cortisones

–

+

–

+

suppressive

–

+

+

6 aldosterone

–

–

++

?n

?n

–

7 Digoxin

+ heart

? –

+

Anti-

–

+

–

Anti-

synthetic E;

E1, E3,

–

+

+

++

++

++

–

+

Oral AS

+

inner

++

++

modulating

+

+++

+=increase; – = lessen; n = apparently neutral? AS=anabolic steroids.

The active hydroxycalciferols are in a sense exocrine ie are produced from ingested vitamin D3 and cholesterol in the skin and kidneys, not from dedicated endocrine glands; but while their synthesis needs no more than an hour of sunlight a week in sunny climates, and modest kidney function, calciferol deficiency is increasingly recognized in those who take little dairy products, and little sunshine. Thus the pituitary, skin, parathyroids, adrenals and gonads are the primary endocrine glands of growth.

The other steroid hormones (like the other major anabolic hormones- insulin and human growth hormone HGH) are endocrine ie are vulnerable to both intrinsic endocrine failure (Hypothalamic-Pituitary-Adrenal- pancreatic-Gonadal ), and to endocrine gland decrease and blockage by infections, cancer, major stress, auto-antibodies or direct trauma.

All these anabolic hormones if swallowed are destroyed by digestion/ 1st-pass hepatic metabolism; thus to achieve the same systemic effect, comparative doses are reported as follows:

ORAL-hepatic

PARENTERAL

TT men

women

120mg/day

5-10mg/day

7-10mg/day

0.5-1mg/d

Estradiol

1-2mg/d

0.03-0.1mg/d

progesterone

5-10mg/d

0.15-0.3mg/d

Cortisone acetate

25-50mg/day

2-5mg/day

fluodrocortone

0.1-0.2mg/d

0.01-.02mg/d?

HGH

autodigested

+- 0.1mg/kg/wk

insulin

autodigested

~40u/day

The vulnerability of oral steroid therapy is illustrated by oral contraception: where taking eg an oral antibiotic can compete for absorption, reducing blood SH levels so that accidental conception occurs. Similarly, a postmenopausal patient with rheumatoid arthritis, on oral (E+P HRT), reports that her analgesic requirements rise while she is on antibiotics.

It is widely overlooked that TT is converted irreversibly by aromatase to E2 in the tissues; but giving E2 does not do the reverse – it suppresses the HPAG and TT production. Thus women need to be given TT with estrogen, but men do not need to be given estrogen – giving them TT increases their E2 levels by about 1/3. This source of E2 may not be enough for balance in women, but reduces their needed dose of administered estrogen; hence in women on a standard 20:1 TT:E2 injection combination, or on combined implants eg TT 50mg + E2 20mg/6months, the blood TT level should be monitored to check that the mean TT is in the physiological range of 1-3.5nmol/L, but the E2 level need not be above perhaps 0.1nmol/L – in fact, to avoid excess fat deposition and breast cancer stimulation, it must not , since TT is supplying E2 direct in target organs.

In TOPICS IN O & G 1998: (ed Julian Bassin: Julmar Communications, Jbg 4th Ed 1998: sponsored by all the RSA gyne Drug Suppliers): Schnitzler CM wrote that “ERT should be given for life, from as early as possible, but even from 80yrs; the elderly not exposed to the sun needing >2000u vit D/day. Sonnendeker on HRT wrote that oral HRT raises both coagulation & renin substrates acutely; EE2 should not be used for ERT; thus he prefers oral ERT except if coagulopathy, liver/biliary/ triglyceride/ or vascular headache problems, when he uses non-oral ERT. Indications for androgens are: poor libido; persistent tiredness & OP; preferring the 25mg TT pellet to oral androgens or imi esters”.

Finally, the physiological logic of parenteral (as opposed to oral) HRT- in this case sex hormone replacement) was already well recognized and marketed over 60 years ago – even in South Africa- in eg the handbook Sex Endocrinology (Schering, New Jersey, 1944) which recommended and listed creams, injections and implants as well as tablets.

An eminent radiologist, Leonard Berlin MD says we have failed to disclose the limitations of screening mammography, namely that mammography will miss 30-70% of breast cancers, and leads to over diagnosis and over treatment.

Dr. Berlin says disclosures of these limitations should be mandated, just like the cigarette and drug warnings that appear on their ads.

Dr. Berlin also points out that 57% of the American women believe that mammograms prevent breast cancer, a misleading message from Breast Awareness Month.

Mammograms are designed to detect cancer, not prevent it. Thinking that a mammogram can prevent breast cancer is like thinking that checking your house annually for broken windows prevents robberies.

In chapter 1 we examined the importance of the blood measurement of HRT – hormone replacement.

This chapter 2 reviews the evidence for the importance of the source, the origin of HRT.

The textbook WOMENS’ BODIES, WOMENS’ WISDOM by ObGyn Prof Christiane Northrup (2nd Ed Piatkus UK 1998) is the only book found which details “the source of all marketed sex hormones”: which at that time, was –
i) EQUINE : MARES’ URINE for Wyeth-Ayerst’s Premarin estrogens;
But “all other prescribed sex hormones are derived from
ii) PLANTS -yams and soya:
the Estrogens – estradiol, estrone, estriol, mestrone, diestranol;
the Progestins – progesterone; norethisterone & dydrogestone;
Testosterone – implants, Sustanon and all the TT esters; and
Tibolone – a weak synthetic estrogen-progestin-androgen:”
(to which RSA has added the African potato/yam for: Moducare); except
iii) SYNTHETICS: the (progestins) levonorgestrol & medroxyprogesterone were
the exceptions, listed as being ‘synthetic’ ie presumably laboratory synthetised.

In April 2008 Northrup reasserts the primacy of for-survival mother Nature’s optimally evolved bioidentical hormones over the 50 year old xenohormones including synthetics – of for-profit Father pharmaceuticsl like Wyeth. see link http://www.drnorthrup.com/news/bioidentical_hormones.php

As Dr Lee Vliet points out in SCREAMING TO BE HEARD (Evans, New York, 2001), “Conjugated estrogens eg Premarin is only 0.5% measurable E2 estradiol; the other 99.5% we cannot routinely measure: 50% is estrone, the rest is scores of other horse estrogens not found in humans”, ie not routinely measurable.
So women are urged by Wyeth, and allowed by the FDA, to take a potent pregnant-mare based compound which ensures some measurable estradiol level, but also ensures potent estrogens at more than hundredfold the bloodlevel of the optimal physiological estradiol level. No wonder oral premarin promotes major complications early in most women, and lifethreatening if continued for more than a dozen years. Why do Regulators (eg the FDA) allow this, except for massive profits for the Regulator, the fiscus, and Industry- Wyeth which creates many jobs, and the Disease Industry that has to take care of the increasing complications of the premarins?

As Vliet’s graphs show, “systemically administered E2 is the ONLY estrogen which raises predominantly the plasma E2 level – the prime youthful estrogen; as opposed to all other (and inferior ) estrogens, which compete with E2 for the estrogen receptor ERs. Premarin especially binds tightly to the ERs”, suppressing and blocking what little E2 older women get or make.

Arising from eg Vliet, there are some six emotive issues to be distinguished in all HRT:
(i) While humans are omnivorous, few usually drink even their own urine, let alone milk, meat or urine from pregnant mares; drinking urine as medicine is condemned by allopathic medicine.
(ii) Thousands of mares across North America are kept pregnant, permanently catheterized,
sedated, tethered to collect their gallons of urine which only Wyeth may (presumably by patent) use (@>$17/liter) to extract Premarin;
(iii) Because of the risk of allergy and eg prion (BSE) infection transmission let alone HIV and newer infections, animals are no longer used as SOURCE of ANY HRT except Premarin; (salmon calcitonin may still be a rare exception). Medicinal products derived even from man (from blood or organs) regularly cause immune or infection disaster..
(iv) Premarin is the only HRT in common use which reportedly has still not been fully characterised – hence Wyeth, via the FDA, has for 50 years deviously prevented any other manufacturer from registering a generic! It is said that at least 40 different steroids have been detected in Premarin; since these are the breakdown products of horse pregnancy, it is not surprising that (while it reduces symptoms and slows osteoporosis), complex Premarin is badly tolerated and rejected by the majority of women (who do not want to feel pregnant).
(v) Recent major RCTs have failed to show benefit from Premarin in older women with vascular or dementing diseases; and
(vi) Up to 80% of women started on oral HRT –( which in the USA is mostly conjugated Estrogens) – abandon it within 3 years…

But Premarin is the sterilized extract of ALL steroid waste products from pregnant mares’ urine, and only about 50% of it’s hormones (E1 and a trace of E2) are identical to human steroids. Other mammals’ meat can produce allergy in humans even when cooked. Hormones surely cannot be cooked or they decompose. Many people are allergic to dairy products; yet women are universally prescribed to drink the product of mares’ urine – and most women abandon it within a few years – wisely so, since the incidence of breast cancer rises steadily with total estrogen dose [Henderson BE , Paganini-Hill A, et al, UCLA: JAMA: 1980;243:1635-9: Menopause, ERT and BRCA 1971-’77:) in 138 BRCA cases, most of risk increase was on Premarin in those with ovaries – which make women intolerant of more than low dose ERT.. RR for BRCA for a ERT cumulative dose >1,500 mg(ie 7yrs) was estimated to be 2.5 in women with ovaries vs 0,7 sans ovaries].

To date the FDA – the US Government- sticks piously to it’s defence to the death of Wyeth’s unique right to produce generic premarin since no-one is yet certain of the precise steroid composition of premarin- which the FDA allows to be marketed only by Wyeth although it is long out of patent, and it’s composition (as a biological urine extract) reputedly varies from batch to batch. http://www.fda.gov/CDER/news/cebackground.htm.
It should be noted that the FDA approved Cenestin soy-based “conjugated estrogens CE ” in 1999, now apparently replaced by Barr Pharmaceuticals with Enjuvia, also a plant-derived formulation of 10 synthetic conjugated estrogenshttp://www.enjuvia.com/patients/about_enjuvia/Default.aspx.

Does it surprise that there are precisely two randomised controlled trials, for 3 -4 months, in 121 women, done in France & USA, published on the clinical benefit of these two (Barr’s) plant-based conjugated estrogens? http://jcp.sagepub.com/cgi/content/abstract/42/3/290.; http://linkinghub.elsevier.com/retrieve/pii/S0378512203002408. American women beware.
But Barrs must be rubbing their hands in glee at the vindication of CE for appropriate use in lower than conventional dose for up to 9 years in the young women in the USA Womens’ Health Initiative (Rossouw ea 2004) RCT.

This international expertexecutive summary confirmsthat muchlower dose HRT (estrogen plus appropriate androgen) (as by the parenteral route) is as beneficial as the conventional oral dose, with far less risks for adverse (fluid retention & liver, breast &thrombosis)effects, and if started early, giving longterm protection against memory loss, fractures and death from vascular disease and breast cancer. The evidence contradictscommon misperceptions and myths:

March 29–30, 2008Summary of the First INTERNATIONAL MENOPAUSE SOCIETY

IMS Global Summit on menopause-related issues: HRT in the early menopause:

. Level A evidence refers to data from randomized controlled trials, whereas Level B evidence comes from case–control/observational studies. As pointed out in the Summit’s title, the focus of discussions was the effects of HRT first administered during the early postmenopausal period.

1. QUALITY OF LIFE AND MENOPAUSE

· In symptomatic postmenopausal women, quality of life and sexuality are improved by HRTand, in the presence of

· In some cultures/ for some women, vaginal bleedings are unacceptable; if bleeding cannot be eliminated, alternatives may be used.

· There is no evidence that so-called ‘natural’ products and unregulated hormone products (compounded bio-identical) significantly improve quality of life.

2. LONGTERM BENEFITS OF HRT POST MENOPAUSE

HRT, coronary heart disease, stroke and thromboembolism

· HRT in women 50–59 years does not increase CHD risk in health and may even decrease risk in this age group[A]

· Estrogen-alone therapy in the age group 50–59 was associated with significantly less coronary calcification (equivalent to a smaller plaque burden), which is consistent with findings of a lower coronary intervention score in women of this age in the WHI study10. [A]

· Early harm (more coronary events during the first 2 years of HRT) was not observed in the early postmenopausal period. The number of CHD events decreased with duration of HRT in both WHI clinical trials[A]

· Data derived from randomized controlled trials in the age group 50–59 are similar to the older observational data suggesting a protective effect of HRT on coronary disease9. [A, B]

· It is unclear at present whether there is a statistical increase in ischemic stoke with standard HRT in healthy women aged 50–59. The WHI data showed no statistically significant increase in risk; nevertheless, even if statistically increased, as found in the Nurses’ Health Study, the low prevalence of this occurrence in this age group makes the attributable risk extremely small. [A,B]

· The risk of venous thrombosis is approximately two-fold higher with standard doses of oral HRT, but is a rare event in that the background prevalence is extremely low in a healthy woman under 60 years of age. [A]

· The risk of venous thrombosis is possibly less with transdermal, compared with oral estrogen therapy [B]

Breast

· There is a wide variation across the world in the incidence of breast cancer and its risk factors.

· There are multiple risk factors for breast cancer, including life-style factors especially alcohol intake, obesity and lack of exercise. These need to be included during counseling to put the magnitude of risk of HRT into perspective [B]

· After 5 years’ use of combined estrogen and progestogen, there is a small increase in risk of breast cancer in North American women of about eight extra cases per 10,000 women per year. However, no significant increase was seen in women without prior use of HRT in the WHI study. [A]

· Estrogen-only use does not cause an increase in breast cancer for up to 7 years21. [A] In observational studies, a small increase in the risk with estrogen-alone therapy appears with long-term use22. [B]

· Women using combined HRT before a diagnosis of breast cancer have a reduced mortality23. [B]

· A decline in the incidence of breast cancer in the USA started before the WHI publication and can be partially related to fluctuation in screening. There has been no decline in breast cancer registration in the UK following the Million Women Study report, nor in Norway, Canada, the Netherlands and countries with stable screening programmes25. [B]

· Combined estrogen and progestogen therapy may cause increased breast density in up to 50% of postmenopausal women, dependent on the regimen (dosage, type of progestogen). The effect of estrogen alone is smaller26. [A]

· The effect on breast density is dose-related. Ultra-low-dose regimes do not cause perceptible change in density[A]

· The average increase in breast density under standard-dose HRT is only about 5–10%28. [A]

· Increased baseline breast density is a risk factor for breast cancer29. There are no data to support a direct association between HRT-induced breast density changes and the risk of developing breast cancer.

· Many women who develop breast cancer have no known risk factors other than growing older. most women with known risk factors do not develop breast cancer.

· HRT has a positive effect on osteoarthritis and the integrity of intervertebral disks.

Cognition

*At present, there is no evidence of substantial cognitive decline across the menopausal transition[A] However, many women experience cognitive difficulties in association with vasomotor symptoms, sleep disturbances & mood changes.

*Verbal memory performance relates with the objective number of hot flushes women experience but not to the number of hot flushes they report.

*Clinical trials find no cognitive benefit among women initiating HRT late postmenopause (i.e. after age 65).

*Observational studies show a decreased risk of Alzheimer’s disease in hormone users and typically involve women who initiated estrogen therapy early in the menopausal transition. [B]

*Limited data exist on the effect of progestogen added to estrogen in the early postmenopause period. Clinical trial data suggest no cognitive benefit with MPA early in the menopause. [A]